Siah2 is an E3 ubiquitin ligase that targets androgen receptor (AR) and plays an important role in the development of castration-resistant prostate cancer (CRPC). However, the regulation of Siah2 in prostate cancer (PCa) is largely unknown. In this study, we used AR-dependent and -independent cells lines to investigate the cellular roles of AR and androgen deprivation therapy (ADT) on Siah2 protein levels and E3 ligase activity using Western blotting and co-immunoprecipitation. We also validated our findings using patient samples taken before and after ADT. Finally, we used xenograft tumor models to test the effects of ADT combined with vitamin K3 (Vit K3) on tumor growth in vivo. Our results showed that AR stabilizes Siah2 protein by attenuating its self-ubiquitination and auto-degradation, likely by blocking its E3 ubiquitin ligase activity. Conversely, ADT decreased Siah2 protein expression but enhanced its E3 ligase activity in PCa cells. Notably, the findings that ADT decreasing Siah2 protein expression were verified in a series of paired PCa samples from the same patient. Additionally, we found that ADT-induced Siah2 activation could be abolished by Vit K3. Strikingly, ADT combined with Vit K3 treatment delayed the occurrence of CRPC and dramatically inhibited the growth of tumor xenografts compared with ADT treatment alone. AR is an inhibitor of Siah2 in PCa, and ADT leads to the continuous activation of Siah2, which may contribute to CRPC. Finally, ADT+Vit K3 may be a potential approach to delay the occurrence of CRPC.

Background Glioma, a common primary brain tumor arising from glial cells, presents significant therapeutic challenges due to its diverse and complex biological behavior. While disulfidptosis has recently emerged as a novel form of cell death, the role of disulfidptosis-related genes (DRGs) in glioma and their relationship with the tumor immune microenvironment remains poorly understood. Methods We analyzed DRGs expression patterns in glioma samples and their correlation with patient survival using data from TCGA, GEO, and CGGA databases. We employed ROC curve analysis to evaluate the diagnostic potential of individual DRGs and identify hub genes. We investigated the relationship between hub gene expression and immune cell infiltration through immune infiltration analysis. Additionally, we conducted drug sensitivity analysis and molecular docking to explore associations between hub gene expression and drug responsiveness. Finally, we validated DRGs expression in glioma samples using RT-PCR and tissue microarrays. Results Among the ten DRGs examined, six genes (OXSM, SLC3A2, RPN1, NDUFS1, GYS1, and LRPPRC) showed significant differential expression in glioma tissues, while four (NCKAP1, NDUFA11, NUBPL, and SLC7A11) did not. Survival analysis revealed that elevated expression of OXSM, RPN1, GYS1, SLC3A2, and NDUFA11 correlated with poor patient outcomes. ROC analysis of both TCGA test and GEO validation sets identified OXSM as a hub gene, with AUC values exceeding 0.88. CGGA database analysis demonstrated higher OXSM expression in GBM compared to LGG, with peak expression in WHO grade IV tumors, significantly correlating with reduced overall survival (p < 0.01). Immune infiltration analysis showed that OXSM expression correlated with various immune cell populations, particularly significantly positively correlated with macrophages M0, M2, and T cells gamma delta, and significantly negatively correlated with monocytes. Drug sensitivity analysis indicated that high OXSM expression enhanced sensitivity to several therapeutic agents. RT-PCR and tissue microarray analyses confirmed elevated OXSM expression in high-grade gliomas. Conclusion Our study identifies OXSM as a key DRG hub gene in glioma, with elevated expression strongly correlating with poor patient prognosis. The observed relationship between OXSM expression and immune cell infiltration suggests its potential role in modulating the glioma microenvironment. These findings advance our understanding of glioma’s molecular mechanisms and may inform the development of novel therapeutic strategies.

Background: The role of tumor inflammatory microenvironment in the advancement of cancer, particularly prostate cancer, is widely acknowledged. ELL-associated factor 2 (EAF2), a tumor suppressor that has been identified in the prostate, is often downregulated in prostate cancer. Earlier investigations have shown that mice with EAF2 gene knockout exhibited a substantial infiltration of inflammatory cells into the prostatic stroma. Methods: A cohort comprising 38 patients who had been diagnosed with prostate cancer and subsequently undergone radical prostatectomy (RP) was selected. These patients were pathologically graded according to the Gleason scoring system and divided into two groups. The purpose of this selection was to investigate the potential correlation between EAF2 and CD163 using immunohistochemistry (IHC) staining. Additionally, in vitro experimentation was conducted to verify the relationship between EAF2 expression, macrophage migration and polarization. Results: Our study demonstrated that in specimens of human prostate cancer, the expression of EAF2 was notably downregulated, and this decrease was inversely associated with the number of CD163-positive macrophages that infiltrated the cancerous tissue. Cell co-culture experiments revealed that the chemotactic effect of tumor cells towards macrophages was intensified and that macrophages differentiated into tumor-associated macrophages (TAMs) when EAF2 was knocked out. Additionally, the application of cytokine protein microarray showed that the expression of chemokine macrophage migration inhibitory factor (MIF) increased after EAF2 knockout. Conclusions: Our findings suggested that EAF2 was involved in the infiltration of CD163-positive macrophages in prostate cancer via MIF. Graphical

Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-β1) through the stem cell factor (SCF)/c-KIT–MAPK–JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo. Thus, these findings revealed a senescence-linked immune–stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.